This application addresses broad Challenge Area (14): Stem Cells, and meets a few specific Challenge Topics: 14-EB-101: Synthetic Delivery Systems for Generating Pluripotent Stem Cells 14-DK-101: Induced pluripotent stem cells - cellular and humanized mouse models of disease 14-DK-102: Discovery of methods to program stem or progenitor cells 06-GM-102: Chemist/biologist collaborations facilitating tool development A series of studies reported that reprogramming of fully differentiated somatic cells into undifferentiated, pluripotent stem cells could be achieved by introducing a number of transcription factors. These induced pluripotent stem (iPS) cells have almost identical pluripotency to embryonic stem (ES) cells. However, there are serious concerns about any approach in which exogenous genetic factors are introduced into somatic cells, and especially when viral integration or foreign genes, which may induce tumors or other adverse effects, are involved. Although non-viral approaches have recently been developed to generate human iPS cells, the source of cells was limited to human embryonic fibroblasts and therefore could not be used to generate disease-specific iPS cells for research or autologous iPS cells for cell therapy. As these are the main advantages of iPS cells over ES cells, additional sources and safer reprogramming methods are needed. At the time of writing, we have successfully reprogrammed mouse fibroblasts into iPS cells using only small molecules. In addition, we have generated iPS cells from peripheral blood of normal volunteers and coronary artery disease (CAD) patients using viral approaches. Accordingly, in this proposal, we will seek to develop novel methods to generate human iPS cells using peripheral blood as a source in combination with small molecular epigenetic regulators. We anticipate that this study will effect a fundamental change in the method of generating human iPS cells and will have enormous impact on disease investigation and clinical application of iPS cells. PUBLIC HEALTH RELEVANCE: A series of studies reported that reprogramming of fully differentiated somatic cells into undifferentiated, pluripotent stem cells, referred to as induced pluripotent stem (iPS) cells, could be achieved by forced expression of pluripotency-related transcription factors. However, the current technology is limited to the use of genetic material (viral or plasmid vectors) for delivery and fibroblasts for the source of parental cells. Accordingly, in this proposal, we will seek to develop novel methods to generate human iPS cells using combinations of small molecular epigenetic regulators with peripheral blood as the cell source.